WO2006014024A1 - Agent thérapeutique pour maladie psychonévrotique - Google Patents

Agent thérapeutique pour maladie psychonévrotique Download PDF

Info

Publication number
WO2006014024A1
WO2006014024A1 PCT/JP2005/014792 JP2005014792W WO2006014024A1 WO 2006014024 A1 WO2006014024 A1 WO 2006014024A1 JP 2005014792 W JP2005014792 W JP 2005014792W WO 2006014024 A1 WO2006014024 A1 WO 2006014024A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
phenyl
alkylene
substituted
amino
Prior art date
Application number
PCT/JP2005/014792
Other languages
English (en)
Japanese (ja)
Inventor
Masami Narita
Kazutoyo Sato
Original Assignee
Ono Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ono Pharmaceutical Co., Ltd. filed Critical Ono Pharmaceutical Co., Ltd.
Priority to JP2006531749A priority Critical patent/JPWO2006014024A1/ja
Priority to EP05770601A priority patent/EP1787657A1/fr
Priority to US11/659,480 priority patent/US20090286862A1/en
Publication of WO2006014024A1 publication Critical patent/WO2006014024A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a preventive and / or therapeutic agent for a neuropsychiatric disease comprising an EP 3 enzyme.
  • Prostaglandin E 2 is known as a metabolite in the arachidonic acid cascade, and its actions are cytoprotective, uterine contraction, analgesic, gastrointestinal peristalsis, arousal, gastric acid It is known to have a secretory inhibitory effect, a blood pressure lowering effect, a diuretic effect, and the like.
  • PGE 2 receptors have subtypes with different roles. There are four subtypes known at present, and they are called EPi, EP 2 , EP 3 and EP 4 (Lipd Mediators Cell Signaling, 1995, Vol. 12, p.379- 391).
  • EP 3 and / or EP 4 antagonists the compounds described in WO03 / 16254 pamphlet, WO02 / 16311 pamphlet, and WO02 / 20462 pamphlet are known.
  • the hormone signaling system mediated by the hypothalamus, pituitary gland, and adrenal cortex The activation of is well known.
  • the corticotropin-releasing factor (CRF) produced in the hypothalamus is stimulated, and the adrenocorticotropic hormone (ACTH) is produced in the pituitary gland.
  • This ACTH stimulates the production of corticosterone in the adrenal cortex.
  • this system is overactivated and corticosterone is secreted excessively, thereby causing various stress responses such as depression, anxiety disorder, psychosomatic disorder and the like.
  • neuropsychiatric disorders includes, for example, tricyclic antidepressants, tetracyclic antidepressants, monoamine oxidase (MAO) inhibitors, serotonin and noradrenaline reuptake inhibitors (SNRI), selective serotonin reuptake inhibitors (SSRI), etc. are used.
  • treatment effects are not sufficient, it takes a long time for the effects to appear, and many side effects include drowsiness, wheezing, constipation, and difficulty in urinating.
  • Benzodiazepines, chenodiazepines, non-benzodiazepines, etc. are used as anxiolytic drugs. However, these also have insufficient therapeutic effects, and as side effects, such as decreased psychomotor function, decreased concentration and attention, drowsiness, lightheadedness, dizziness, headache, and amnesia. Disclosure of the invention
  • An object of the present invention is to provide a preventive and / or therapeutic agent for a neuropsychiatric disease based on an unprecedented mechanism of action.
  • the present inventors have found that the EP 3 antagonist is useful as a preventive and / or therapeutic agent for neuropsychiatric diseases, and completed the present invention.
  • a preventive and / or therapeutic agent for a neuropsychiatric disease comprising an EP 3 enzyme gonist,
  • the neuropsychiatric disease is a disease caused by stress, Preventive and / or therapeutic agent for neuropsychiatric diseases,
  • neuropsychiatric disorder is depression, anxiety disorder, or psychosomatic disorder caused by stress
  • the anxiety disorder is selected from obsessive compulsive disorder, panic disorder, post-traumatic stress disorder, generalized anxiety disorder, mixed anxiety depression disorder, social phobia, social anxiety disorder and social phobia
  • Psychosomatic disorders include autonomic dysfunction, menopause, hypertension, hypotension, angina, bronchial asthma, hyperventilation syndrome, irritable bowel syndrome, gastric ulcer, duodenal ulcer, headache, migraine, irritable bladder, Selected from enuresis, insomnia, alopecia areata, diabetes, premenstrual syndrome ⁇ dysmenorrhea, infertility, anxiety, alcoholism, anorexia nervosa, bulimia, meniere syndrome, cervical-arm syndrome, and indefinite complaints
  • the agent for preventing and / or treating a neuropsychiatric disease according to the above [3], which exhibits one or more symptoms [9] Furthermore, a tricyclic antidepressant, a tetracyclic antidepressant, a monoamine Xidase inhibitor, serotonin and noradrenaline reuptake inhibitor, selective cello Tonin reuptake inhibitor, 5- HT1A receptor agonist, GAB A receptor agonist, dop
  • EP 3 Engonist is general formula (I)
  • EP 3 antagonist is represented by the general formula (II)
  • [23] A spirit characterized by administering to a mammal an effective amount of a compound represented by general formula (I) or general formula (II), a salt thereof, a solvate thereof, or a prodrug thereof.
  • a method for the prevention and / or treatment of nervous system diseases
  • the EP 3 enzyme gonist may be any compound as long as it has antagonistic activity against EP 3 , and is not limited by the presence or absence or strength of antagonistic activity against other EPs. .
  • R 1 one COOH, one COOR 4, one CH 2 OH, one C_ ⁇ _NR 5 S_ ⁇ 2 R 6, one C_ ⁇ _NR 7 R 8 ⁇ one CH 2 NR 5 S0 2 R 6 , one CH 2 NR 9 C 0 R 10 , -CH 2 NR 9 CONR 5 S0 2 R 6 , 1 CH 2 SO 2 NR 9 C ⁇ R 10 , 1 CH 2 OCONR 5 S 0 2 R 6 , tetrazole, 1, 2, 4 1-oxadiazo 5-lu, 1, 2, 4 4-oxadiazo 5-luone, 1, 2, 4, 4-thiadiazol 5-one, 1, 3-thiazolidine 1, 2- 4-dione, or 1, 2, 3, 5—Oxathia diazo 1-lu
  • R 4 represents C 1-6 alkyl or one (Cl-4 alkylene) one R 11 , R 11 represents a hydroxyl group, Cl-4 alkoxy, one C0OH, C 1-4 alkoxycarbonyl, or one CONR 7 R 8 represents
  • R 5 represents a hydrogen atom or C 1-6 alkyl
  • R 6 is (i) C 1-6 alkyl
  • R 7 and R 8 are each independently (i) a hydrogen atom
  • R 12 groups substituted or unsubstituted C 3-15 monocyclic, bicyclic or tricyclic carbocyclic ring, or 3-15 membered monocyclic, bicyclic or tricyclic A heterocycle of the ring, or
  • R 9 represents a hydrogen atom or C 1-6 alkyl
  • R 1Q is (0 hydrogen atom
  • R 12 represents C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl substituted by a heterocyclic ring of the ring, R 12 is (a) C 1-6 alkyl, (b) C 1-6 alkoxy, (c) C 1-6 alkyl thio, (d) a halogen atom, (e) CF 3 , () ciano, (g ) Nitro, (h) Hydroxyl group, (i) One COOR 13 , (j) -NHCOR 13 , (k) —S0 2 R 14 , (1) —NR 15 R 16 , (m) Cl to 4 alkyl or An oxo-substituted or unsubstituted C3-ma monocyclic carbocycle,
  • R 13 represents a hydrogen atom, Cl-4 alkyl, phenyl, phenyl (Cl-4) alkyl,
  • R 14 represents C 1-4 alkyl
  • R 15 and R 16 each independently represent a hydrogen atom, C 1-4 alkyl, phenyl, phenyl (Cl-4) alkyl,
  • R 17 represents C 1-4 alkyl or phenyl
  • A is (i) a single bond
  • Alkylene, alkenylene and alkynilesi in A may be substituted with 1 to 6 groups selected from the following substituents (a) to (i):
  • R 2 It represents a hydrogen atom, C L ⁇ 4 alkyl, an S_ ⁇ 2 (Cl ⁇ 4) alkyl or C2 ⁇ 5 Ashiru,
  • R 21 represents a hydrogen atom or C 1-4 alkyl
  • Cyc l is Cl ⁇ 6 alkyl, C. 1 to 6 alkoxy, C. 1 to 6 alkylthio, C2-6 alkenyl, C2-6 alkynyl, halogen atom, CHF 2, CF 3, group 1-4 pieces selected from nitro and Shiano Represents a substituted or unsubstituted C3-7 monocyclic carbocyclic ring, or a 3-7 membered monocyclic heterocyclic ring, and ring B is a C3-l2 monocyclic or bicyclic carbocyclic ring, Or a 3- to 12-membered monocyclic or bicyclic heterocyclic ring,
  • 13 ⁇ 4 2 represents O 1-6 alkyl, Cl-6 alkoxy, C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl, halogen atom, CHF 2 , CF 3 , ditro, cyano, phenyl or oxo;
  • n 0, 1 or 2
  • n 1 or 2
  • n 0, 1 or 2;
  • Q is (1) (i) — (C 1-4 alkylene, C 2-4 alkenylene or C 2-4 alkynylene)
  • R 22 represents a hydrogen atom, C 1-4 alkyl, mono S0 2 — (C 1-4) alkyl or C 2-5 acyl.
  • R 23 represents a hydrogen atom, Cl-4 alkyl, phenyl or phenyl (C 1-4) alkyl;
  • R 24 and R 25 each independently represents a hydrogen atom, C 1-4 alkyl, Cyc 4 or (Cl-4 alkylene) 1 Cyc 4;
  • R 26 represents C 1-4 alkyl or Cy c 4
  • R 27 represents a hydrogen atom, Cl to 4 alkyl, 10 R 29 or Cy c 4
  • R 28 represents C 1 to 4 alkyl, Cyc 4 or 1 (Cl 4 alkylene) 1 Cyc 4,
  • R 29 represents a hydrogen atom, Cl-4 alkyl, Cyc 4 or (C 1-4 alkylene) 1 Cyc 4;
  • R 30 is C 1-8 alkyl, Cl-8 alkoxy, C 1-8 alkylthio, halo Gen atoms, CF 3, OCF 3, SCF 3, CHF 2, ⁇ _CHF 2, SCHF 2, water group, Shiano, nitro, One NR 31 R 32, one CONR 31 R 32, formyl, C2-5 Ashiru, hydroxy (Cl-4) alkyl, C1-4 alkoxy (Cl-4) alkyl, C1-4 alkylthio (C1-4) alkyl, one (C1-4 alkylene) — CONR 31 R 32 , one S0 2 (C1-4) alkyl, —NR 23 CO— (C1-4) alkyl, one NR 23 S0 2 — (Cl-4) alkyl, benzoyl, oxo, C3-7 monocyclic carbocycle, 3— 7-membered monocyclic heterocycle, — (C 1-4 alkylene) 1 NR 31 R 32 , -M- (C3-7 monocyclic carbo
  • M is 0—, 1 S—, Cl-4 alkylene, 1 0— (C 1-4 alkylene) —, —S— (C 1-4 alkylene) 1, 1 (C 1-4 alkylene) Or one (Cl-4 alkylene) one S—
  • R 31 and R 32 each independently represents a hydrogen atom or C 1-4 alkyl
  • Cy c 2 is substituted by 1-5 R 3 ° or unsubstituted C 3-15 monocyclic, bicyclic or tricyclic carbocyclic ring, or 3-15 membered monocyclic, bicyclic or tricyclic Represents a heterocycle of the ring,
  • Cy c 3 is substituted by 1-5 R 3 ° or unsubstituted C 3-15 monocyclic, bicyclic or tricyclic carbocyclic ring, or 3-15 membered monocyclic, bicyclic or Represents a tricyclic heterocycle,
  • Cyc 4 represents an unsubstituted C3-12 monocyclic or bicyclic carbocyclic ring, or a 3-12 membered monocyclic or bicyclic heterocyclic ring substituted by 1-5 R 3D ,
  • T is one 0—, one NR 22 —, one 0— (Cl-4 alkylene) one, one S ( ⁇ ) p — (Cl-4 alkylene) one, or one NR 22 — (Cl-4 alkylene) one Expression,.
  • Cyc 5 is substituted by 1-5 R 3 ° or unsubstituted 3-3
  • L one 0- or a NR 23 - represents,
  • Cyc 6-1 represents a phenyl or benzyl that is always substituted with at least one R 3 °
  • Cyc 6—2 is 1 to 5 R 3 . Represents a C 3-6 monocyclic carbocycle substituted or unsubstituted by
  • Cyc 6-3 represents a C 7-15 monocyclic, bicyclic or tricyclic carbocycle substituted or unsubstituted by 1-5 R 3 °
  • R 33 and R 34 each independently represent a hydrogen atom, Cl-4 alkyl, phenyl or benzyl, or
  • NR 33 R 34 represents a nitrogen atom, or a 3- to 6-membered monocyclic heterocycle which may contain one heteroatom selected from a nitrogen atom, an oxygen atom or a sulfur atom,
  • D is an atom selected from (1) carbon atom, nitrogen atom, oxygen atom and sulfur atom
  • An atom selected from a carbon atom, a nitrogen atom, an oxygen atom and a sulfur atom is a linked chain consisting of 3 to 6 members, and the chain may contain a double bond or a triple bond, and the linked chain May be substituted with 1 to 12 R 4 °, and further R 4 ° substituted with the same atom to which R 3 is bonded together with R 42 which is a substituent of R 3 May form one (CH 2 ) y — (wherein y represents 1 to 4), or
  • R 40 is (a) C 1-8 alkyl, (b) C 2-8 alkenyl, (c) C 2-8 alkynyl, (d) oxo, (e) halogen atom, (> CF 3 , (g) Hydroxyl group, (h) Cl-6 alkoxy, (i) C 2-6 alkenyloxy, (j) C 2-6 alkynoxy, (k) OCF 3 , (DS (0) p — (C 1- 6) Alkyl, (m) — S (0) p — (C 2-6) Alkenyl, (n) — S (0) p — (C2-6) Alkynyl, ( 0 ) C2-5 Acyl, (p ) Cy C 9, (q) C 1-4 alkoxy (C 1-4) alkoxy, (r) halogen atom, CF 3 , OCF 3 , hydroxyl group, cyan, Cl-4 alkoxy, mono S (0) p- ( C 1-6) alkyl,
  • the two R 4 ° together with the atoms of the linking chain to which they are attached are selected from C3 to l5 monocyclic, bicyclic or tricyclic carbocyclic or 0, S, S0 2 and N 3 to 15-membered mono-, bi- or tricyclic rings containing 1 or 2 heteroatoms Of or a heterocyclic, addition carbocyclic ring and heterocyclic ring C 1 to 4 alkyl, C l to 4 alkoxy, C 2 to 5 Ashiru, S_ ⁇ 2 (C L ⁇ 4 alkyl), phenyl, Contact and phenyl (C l to 4) may be substituted with 1 to 3 groups selected from alkyl,
  • Cyc 9 represents 1 to 5 R 41 -substituted or unsubstituted C 3-6 monocyclic carbocycles or 3-6 membered monocyclic heterocycles,
  • R 41 is C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkoxy (C 1-4) alkyl, halogen atom, CF 3 , OCF 3 , S CF 3 , hydroxyl group, cyan , Formyl, C2-5 acyl, S0 2 — (C 1-4) alkyl, _NR 23 C 0 (C 1-4) alkyl, benzoyl or oxo,
  • R 3 is (1) C 1-6 alkyl, or
  • R 42 is (a) C 1-6 alkyl, (b) C 1-6 alkoxy, (c) C 1-6 alkyl thio, (d) a halogen atom, (e) Ciano, (£) CF 3 , ( g ) CHF 2 , (h) 0 CF 3 , (i) 0 CHF 2 , j) S CF 3 , (k) —NR 43 R 44 , (1) S0 2 R 45 , (m) — NR 46 C 0 R 47 , (n) hydroxyl group, (o) oxo, (p) C 1-4 alkoxy (C 1-4) alkyl, (q) Cy c 10, (r) C 1-6 alkylene mono Cyc 10, (s) -CO-Cy c 10, (t)-W— Cy c 10, (u) — (C 1-6 alkylene) One W—Cy c 10, (v) — W— (C 1-6 alkylene) ) One Cyc 10 or (
  • R 43 and R 44 each independently represents a hydrogen atom or C 1-4 alkyl
  • R 45 represents C 1-4 alkyl
  • R 46 represents a hydrogen atom or C 1-4 alkyl
  • R 47 represents a hydrogen atom or C 1-4 alkyl
  • Cy c 10 is substituted with 1 to 5 groups selected from the substituents shown in the following (a) to (j), or unsubstituted C3 to l 2 monocyclic or bicyclic carbon Represents a ring, or a 3-12 membered mono- or bicyclic heterocycle:
  • R 48 represents a hydrogen atom or C 1-4 alkyl.
  • Compound IA (Hereinafter abbreviated as Compound IA), a salt thereof, a solvate thereof, or a prodrug thereof.
  • n 1 or 2
  • Q is (1) (i) one (C 1-4 alkylene, C 2-4 alkenylene or C 2-4 alkynylene) one Cy c 2,
  • (V) a C 3-7 monocyclic carbocyclic ring substituted with 1 to 5 R 3 °, and one R 3 ° must be substituted at a position other than position 1 of the ring, or 3-6 membered monocyclic bicyclic ring,
  • D is (1) an atom selected from a carbon atom, a nitrogen atom, an oxygen atom, and a sulfur atom. It is a linked chain consisting of 1 or 2 members, and the chain may contain a double bond or a triple bond.
  • the linking chain may be substituted with 1 to 4 R 4 °, and (2) is a linking chain consisting of 3 to 6 atoms selected from a carbon atom, a nitrogen atom, an oxygen atom, and a sulfur atom.
  • linking chain may be substituted with 1 to 12 R 4 °, and further, an atom to which R 3 is bonded in the linking chain R 4G substituted with R 3 may be combined with R 42 which is a substituent of R 3 to form one (CH 2 ) y — compound IA,
  • n 1 or 2
  • D is a connecting chain consisting of 3 to 6 atoms selected from (2) carbon atom, nitrogen atom, oxygen atom and sulfur atom, and the chain may contain a double bond or a triple bond 3 ⁇ 4
  • the linking chain may be substituted with 1 to 12 R 4Q s .
  • R 4 ° substituted with an atom to which R 3 is bonded in the linking chain is a substituent of R 3
  • Compound IA which may be combined with R 42 to form one (CH 2 ) y —, in general formula (I), n is 1 or 2, Q is (3) (i) C2-6 alkenyl,
  • D is (1) an atom selected from a carbon atom, a nitrogen atom, an oxygen atom, and a sulfur atom. It is a linked chain consisting of 1 or 2 members, and the chain may contain a double bond or a triple bond.
  • the linking chain may be substituted with 1 to 4 R 4 ° compounds IA ⁇
  • n 0,
  • D is (1) an atom selected from the group consisting of a carbon atom, a nitrogen atom, an oxygen atom and a sulfur atom. It is a linked chain consisting of 1 or 2 members, and the chain may contain a double bond or a triple bond. The chain may be substituted with 1 to 4 R 4 °, and (2) an atom selected from a carbon atom, a nitrogen atom, an oxygen atom and a sulfur atom 3 to
  • R 4 ° substituted for the atom to which R 3 is bonded R 4 is a substituent of R 3
  • D is a connecting chain consisting of 7 to 10 atoms selected from (3) carbon atom, nitrogen atom, oxygen atom and sulfur atom, and the chain may contain a double bond or a triple bond.
  • linking chain may be substituted by 1-20 R 4 °, R 4 ° is that replacing the atom attached is linking chain in R 3 to be al, substituents R 3 der Compound IA that may form one (CH 2 ) y — together with R 42 .
  • D is a connecting chain consisting of 1 or 2 members selected from (1) a carbon atom, a nitrogen atom, an oxygen atom and a sulfur atom, May contain a double bond or a triple bond, and the linking chain may be substituted with 1 to 4 R 4 °, and
  • D is a connecting chain consisting of 3 to 6 members of an atom selected from (2) carbon atom, nitrogen atom, oxygen atom and sulfur atom, and the chain may contain a double bond or a triple bond.
  • the linking chain may be substituted with 1 to 12 R 4Q.
  • R 4 ° substituted with the atom to which R 3 is bonded may form one (CH 2 ) y — together with R 42 , the substituent of R 3. Good compounds are mentioned.
  • Preferred combinations of groups in the above-mentioned compounds represented by the general formula (I) shall follow the combinations described in WO03 / 016254.
  • R 1 ′ represents a hydrogen atom or C 1-4 alkyl
  • R 2 ′ represents phenyl, naphthyl, benzofuranyl, or benzophenyl which is unsubstituted or substituted with 1 to 2 groups selected from C 1-4 alkyl and halogen atoms;
  • Q represents (i) 1 CH 2 —O 1 Cyc l, (ii) —CH 2 —Cy c 2 ⁇ or (iii) —L, 1 Cy c 3 ′,
  • Cy c 1 represents phenyl or pyridyl which is unsubstituted or substituted by 1 to 2 R 4 's
  • C yc 2 ' represents an indrill that is unsubstituted or substituted with 1 to 2 R 4 ' s
  • C yc 3 ' represents phenyl substituted by 1 to 2 R 4 ' s
  • L ' represents 1 0- or 1 NH-
  • R 3a ′ and R 3b ′ each independently represent a hydrogen atom or C 1-4 alkyl, or
  • R 3a 'and R 3b ' and the carbon atom to which they are attached represents tetrahydro-2H monopyran
  • m ′ 2 or 3
  • n ' represents 0, 1, or 2
  • R 4 ′ represents C 1-4 alkyl, C 1-4 alkylthio, a halogen atom, or cyan, or when Cyc 3 ′ represents phenyl substituted by two R 4 ′, Two R 4 'groups with a phenyl ring May be represented. ), A salt thereof, a solvate thereof, or a prodrug thereof.
  • the definitions of the groups and substituents shown in the general formula (II) are as follows.
  • C 1-4 alkyl represents methyl, ethyl, propyl, butyl, or isomers thereof.
  • C 1-4 alkylthio represents methylthio, ethylthio, propylthio, butylthio, or isomers thereof.
  • a halogen atom means fluorine, chlorine, bromine, or iodine.
  • Preferred R 1 ′ of the present invention includes a hydrogen atom, methyl, or ethyl.
  • Preferred n ′ in the present invention is 0 or 2.
  • Preferred examples of the substituent for the ring represented by R 2 ′ of the present invention include methyl and fluorine.
  • Preferred R 3a ′ and R 3b ′ of the present invention are each independently hydrogen atom, methyl, isobutyl, or R 3a ′ and R 3b ′ together with the carbon atom to which they are bonded, and tetrahydro 2 H— Piran is mentioned. More specifically, Preferred R 4 ′ of the present invention includes methyl, thiomethyl, fluorine, chlorine or cyano.
  • EP 3 antagonists compounds described in pamphlet of W099 / 47497, compounds described in pamphlet of WO00 / 20371, compounds described in pamphlet of WO01 / 62708, compounds described in pamphlet of WO02 / 16311 And compounds having EP 3 antagonistic activity among the compounds described in WO02 / 20462 pamphlet.
  • an EP 3 antagonist more preferably, 3— (2-((((1 R) — 1- (3,5-dimethylphenyl) —3-methylmethyl) amino) carbonyl) One (5-Fluoro-2-methylphenoxymethyl) ⁇ nyl) propanoic acid, 3— (2-(((1 R) 1 3-methyl-1- 1- (3,5-dimethylphenyl) butyl) strong rubamoyl) 4-1 4 (2,5-difluorophenoxymethyl) phenyl) propane Acid, or 3— (2-(((1 R)-3 1 methyl 1 (3, 5-dimethylphenyl) ptyl) rubamoyl) 1 4 1 (2,5-dimethylphenoxymethyl) phenyl ) Propanoic acid, their salts, their solvates, or their prodrugs, especially 3— (2 1 ((((1 R) — 1— (3,5-dimethylphenyl) 1 3 —Meth
  • the alkyl group includes straight-chain and branched-chain groups.
  • isomers in rings and condensed rings (E, Z, cis, trans isomers), isomers due to the presence of asymmetric carbons (R, S isomers, isomers, enantiomers, diastereomers), optical rotation All optical isomers (D, L, d, 1), polar bodies (high polarity, low polarity) by chromatographic separation, equilibrium compounds, compounds in any ratio, and racemic mixtures Included in the invention.
  • Z represents a single configuration, a single configuration or a mixture thereof, and Z represents a mixture of a single configuration and a 5-configuration.
  • the compound according to the present invention is converted into a pharmaceutically acceptable salt by a known method.
  • the salt is preferably non-toxic and water-soluble. Suitable salts include alkali metal (potassium, sodium, etc.) salts, alkaline earth metals (calcium, magne Salt), ammonium salts, pharmaceutically acceptable organic amines (tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine) And salts of tris (hydroxymethyl) methylamine, lysine, arginine, N-methyl-1-D-glucamine, and the like.
  • the acid addition salt is preferably non-toxic and water-soluble.
  • Suitable acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, or acetate, trifluoroacetate, lactate, tartrate, oxalate.
  • inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, or acetate, trifluoroacetate, lactate, tartrate, oxalate.
  • fumarate maleate, citrate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, gluconate
  • organic acid salts are mentioned.
  • the compounds according to the present invention and their salts can also be converted into solvates, respectively.
  • the solvate is preferably non-toxic and water-soluble.
  • suitable solvates include solvates such as water and alcohol solvents (for example, ethanol).
  • the prodrug of the compound according to the present invention refers to a compound that is converted into a compound represented by general formula (I) or general formula ( ⁇ ) by a reaction with an enzyme, gastric acid or the like in vivo.
  • the amino group is acylated, alkylated, or phosphorylated.
  • Compound for example, the amino group of the compound represented by the general formula (I) is eicosanylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1, 1-dioxolene, 4-yl) Methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, viva Royloxymethylated, acetyloxymethylated, tert-butylated compounds, etc.); when the compounds represented by general formula (I) and general formula (II) each have a hydroxyl group, the hydroxyl group is acylated or alkylated.
  • Phosphorylated, borated compounds for example, the hydroxyl groups of the compounds represented by general formula (I) and general formula (II) are acetylated, palmitoylated, propanoylated, bivalylated, succinylated,
  • the carboxy group is esterified
  • Amidated compounds for example, the force of the compound represented by the general formula (I) and the general formula (II), the ruxoxy group, Telluration, Isopropyl esterification, Phenyl esterification, Carboxymethyl esterification, Dimethylaminomethyl esterification, Bivaloyloxymethyl esterification, Ethoxycarbonyloxetyl esterification, Phthalidyl esterification, (5-methyl-2 -Oxo- 1, 3 -dioxolene 41-yl) Methyl esterification, cyclohexyloxy
  • the compound represented by the general formula (I) can be produced by the production method described in WO 03/016254 and the production methods described in the examples.
  • R 1 ′ is a hydrogen atom, that is, the general formula (Ila)
  • R lb ′ represents C 1-4 alkyl
  • R lb ′ represents C 1-4 alkyl
  • Alkaline hydrolysis reactions are known, for example, in an organic solvent miscible with water (methanol, ethanol, tetrahydrofuran, dioxane, or a mixed solvent thereof), alkali (sodium hydroxide, potassium hydroxide, potassium carbonate). 1) to 90 ° C. using an aqueous solution of
  • the compound represented by the general formula (lib) can be produced, for example, according to the following reaction process formulas A to D.
  • Q 1 ' represents (i) — CH 2 — 0— Cyc 1, or (ii) — CH 2 — Cyc2'
  • Y 1 ′ represents a hydroxyl protecting group
  • Y 2 ' represents a protecting group for an amino group
  • Ms represents a mesyl group
  • T f represents trifluoromethylsulfonyl
  • X ′ represents a halogen atom
  • the reaction product is obtained by ordinary purification means, for example, distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin. It can be purified by a method such as scavenger resin or column chromatography, washing or recrystallization. Purification may be performed for each reaction or after completion of several reactions.
  • purification means for example, distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin. It can be purified by a method such as scavenger resin or column chromatography, washing or recrystallization. Purification may be performed for each reaction or after completion of several reactions.
  • the toxicity of the compound according to the present invention was sufficiently low, and it was confirmed that the compound was sufficiently safe for use as a medicine.
  • the compound according to the present invention is considered to be useful for the prevention and / or treatment of diseases caused by stress, and neuropsychiatric diseases such as depression, anxiety disorders, and psychosomatic disorders.
  • a disease caused by stress refers to a disease caused by a physical and / or mental stress state, and includes central and Z or systemic diseases.
  • depression includes depression episodes, dysthymia, mood circulatory disorder, bipolar affective disorder, or manic depression.
  • anxiety disorder is selected from obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, generalized anxiety disorder, mixed anxiety depression disorder, social phobia, social anxiety disorder and social phobia
  • psychosomatic disorders include autonomic dysfunction, menopause, hypertension, hypotension, angina pectoris, bronchial asthma, hyperventilation syndrome, irritable bowel syndrome, gastric ulcer / duodenal ulcer, headache, migraine, hypersensitivity Urinary bladder, enuresis, insomnia, alopecia areata, diabetes mellitus, premenstrual syndrome, dysmenorrhea, infertility, anxiety, alcoholism, anorexia nervosa, bulimia, Meniere syndrome, neck-arm syndrome It also includes cases that exhibit one or more symptoms selected from the above.
  • the above depression, anxiety disorder, or psychosomatic disorder also includes cases that develop due to stress.
  • the compounds according to the present invention, their salts, their solvates, or their prodrugs are: (1) complementation and / or enhancement of the prevention and / or treatment effect of the therapeutic agent of the present invention, (2) Dynamics of the therapeutic agent of the invention ⁇ Improvement of absorption, reduction of dosage, and / or (3) In order to reduce the side effects of the therapeutic agent of the present invention, it may be administered in combination with other drugs .
  • the compound of the present invention, a salt thereof, a solvate thereof, or a combination drug of these prodrugs and other drugs may be administered in the form of a combination drug containing both components in one preparation. Moreover, you may take the form administered as a separate formulation. When administered in separate formulations, simultaneous administration and administration by time difference are included. In addition, administration by the time difference may be performed by administering the therapeutic agent of the present invention first, and then administering other agents later, or administering other agents first, and administering the therapeutic agent of the present invention later. Often, each method of administration may be the same or different.
  • the disease that exhibits the preventive and / or therapeutic effect by the above-mentioned concomitant drug is not particularly limited, and any disease that complements and / or enhances the preventive and / or therapeutic effect of the therapeutic agent of the present invention may be used.
  • antidepressants for example, tricyclic antidepressants, tetracyclic antidepressants.
  • Drugs monoamine oxidase (MA ⁇ ) inhibitors, serotonin and noradrenaline reuptake inhibitors (SNRI), selective serotonin reuptake inhibitors (SSRI), 5- HT1A receptor agonists, GA BA receptor agonist Drugs, dopamine receptor antagonists, psychostimulants, anti-anxiety drugs, antipsychotic drugs, mitochondria benzodiazepine receptor (MBR) ligands, NK 1 antagonists, sigma receptor agonists, serotonin nervous system agonists, corticotropin releasing out factor (CRF) receptor antagonists, proton pump inhibitors, His evening Min Eta 2 receptor antagonists, Ml receptor antagonists such as, E Pi antagonists, and other stress-related diseases Ryoyaku and the like.
  • MLR mitochondria benzodiazepine receptor
  • NK 1 antagonists sigma receptor agonists
  • fluoxamine maleate paroxetine hydrochloride, fluoxetine hydrochloride, citalopram hydrochloride, minaprine hydrochloride, sibutramine hydrochloride, tee Nepuchin, nefazodone hydrochloride, sertraline hydrochloride, trazodone hydrochloride), 5-HT 1A receptor agonists (e.g., Mi Rutazapin), GAB A receptor agonists (e.g., Purobagai de, gabapentin, Topiramate), dopamine receptor antagonists (eg, risberidone, olanzapine, quetiapine fumarate, ziprasidone hydrochloride hydrate, pramipexo hydrochloride)
  • 5-HT 1A receptor agonists e.g., Mi Rutazapin
  • GAB A receptor agonists e.g., Purobagai de, gabapentin, Topiramate
  • Examples of psychostimulants include methylphenidate hydrochloride and pemoline.
  • Anti-anxiety drugs include, for example, benzodiazepines (e.g., alprazolam, oxazebam, oxazolam, cloxazolam, chlorazepate disulfide, chlordiazepoxide, diazepam, tofuisopam, triazolam, prazepam, fluzazepam, , Frutoprazepam, Bromazepam, Mexa V ram, Medazepam, Oral frazepate ethyl, Lorazepam, Clonazebam, Azinazolam mesylate), Chenodiazepines (eg, etizolam, crotiazepam) Hydroxylzine, buspirone, venlafaxine, tropisetron hydrochloride, arosetron, tyagabine hydrochloride).
  • benzodiazepines e.g., alprazolam, oxazeb
  • Antipsychotics include, for example, sulpiride, trazodone hydrochloride, serotonin / dopamine antagonists (eg risperidone, velopirone hydrochloride hydrate, quetiapine fumarate, olanzapine).
  • gastrointestinal function regulators examples include trimebutine maleate and polycarbophil calcium.
  • An example of a 5-HT 3 antagonist is arosetron.
  • HT 4 agonists include, for example, tegaserod, cysabride, and citrate mosapride.
  • stress diseases include, for example, tandospirone citrate, resoptron, igmesin, AP-521, PLD-116, ilaprazol, ⁇ 3412, DMP-696, ME-3412, YJA_20379-8, pirenzepine hydrochloride , Lansoprazole, Dosmalfate and osemozotan.
  • Anti-depressive drugs include sultopride hydrochloride, carbazepine, and sodium valproate.
  • the compounds according to the present invention are safe and low toxic prevention and / or treatment for stress-related diseases, depression, anxiety disorders, or psychosomatic disorders Useful as an agent.
  • antidepressants and anti-anxiety drugs which are used in the treatment of neuropsychiatric disorders, have side effects such as drowsiness and muzzling.
  • the compounds according to the present invention have EP 3 antagonistic activity. Because they have different mechanisms of action, they do not show the side effects caused by existing drugs.
  • a salt thereof, a solvate thereof, or a broad drug thereof is used as an active ingredient in a medicine, it is used alone or in combination with various pharmacologically acceptable pharmaceutical adjuvants.
  • mammals eg, human non-human animals, etc.
  • it is administered to humans.
  • the dosage of such compounds varies depending on age, weight, symptoms, therapeutic effects, administration method, treatment time, etc., but is usually about 1 g per adult.
  • the dosage varies depending on various conditions such as the medical condition and age, so that an amount smaller than the above dosage may be sufficient, or administration beyond the range may be necessary.
  • human doses can be predicted or determined from non-human animal doses, for example, rat doses, on the basis of so-called scientific evidence based on empirical or empirical evidence.
  • desipramine hydrochloride was effective at 20 mg / kg per day.
  • the daily dose of desipramine hydrochloride for adults is 100-20 Omg [Physicians' Desk Reference, 57Edition, 2003].
  • the daily dose for humans is 5 to 10 times the amount excluding the weight ratio of rat dose (ie 20 mg).
  • the daily dose of humans is the weight ratio of the dose of rats. It can be estimated as 1 to 5 to 10 times the amount removed. That is, about 1 Omg to about 10 Omg per day can be determined to be a preferred dose.
  • the dose of the compound according to the present invention in the prevention and / or treatment of neuropsychiatric diseases is preferably 1 to 4 times a day by oral administration. More preferably from about 5 mg to about 30 Omg, particularly preferably from about 10 mg to about 10 Omg, most preferably from about 1 Omg to about 5 Omg. is there. It is also preferred to include about lmg to about 10 Omg of a compound according to the invention per solid formulation. More preferably, about 2.5 mg / 1 solid formulation, about 5 mg / l solid formulation, about 10 mg / l solid formulation, about 25 mg / l solid formulation, and about 5 Omg / 1 solid formulation.
  • the solid preparation tablets and capsules are preferable, particularly tablets are preferable. It is preferable to administer 1 to 4 tablets per day, 1 to 3 times a day, and 1 to 12 tablets per day.
  • a compound according to the present invention When administering a compound according to the present invention, a salt thereof, a solvate thereof, or a combination drug of these drug drugs and other drugs, it is used for oral administration. Used as solid preparations, liquids for internal use, injections for parenteral administration, external preparations, suppositories, eye drops, inhalants, etc.
  • Examples of solid preparations for internal use for oral administration include tablets, pills, capsules, powders, and condyles.
  • Capsules include hard gabbels and soft capsules.
  • Tablets include sublingual tablets, intraoral adhesive tablets, intraoral quick disintegrating tablets and the like.
  • one or more active substances may be used as they are, or excipients (lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binders (hydroxypropylcellulose, Polyvinylpyrrolidone, magnesium aluminate metasilicate, etc.), disintegrating agents (fibrin calcium calcium glycolate, etc.), lubricants (magnesium stearate, etc.), stabilizers, solubilizing agents (glutamic acid, aspartic acid, etc.), etc. It is formulated and used according to conventional methods.
  • a coating agent sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethyl cell mouth-sphthalate, etc.
  • a coating agent sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethyl cell mouth-sphthalate, etc.
  • capsules of absorbable substances such as gelatin.
  • the sublingual tablet is produced according to a known method.
  • one or more active substances with excipients lactose, mannitol, glucose, microcrystalline cellulose, colloidal silica, starch, etc.
  • binders hydroxypropylcellulose, polyvinylpyrrolidone, magnesium aluminate metasilicate) Etc.
  • disintegrating agents starch, L-hydroxypropylcellulose, carboxymethylcellulose, croscarmellose sodium, calcium calcium glycolate, etc.
  • lubricants magnesium stearate, etc.
  • swelling agents hydroxypropylcellulose, Hydroxypropyl methylcellulose, Carbopol, Carboxymethylcellulose, Polyvinyl alcohol, Xanthan gum, Guaga Etc.
  • swelling aid glucose, fructose, mannitol, xylitol, erythritol, maltose, trehalose, phosphate, kenate, cate, glycine, glutamic acid,
  • Oral adhesive tablets are prepared according to known methods.
  • one or more active substances with excipients lactose, mannitol, glucose, microcrystalline cellulose, colloidal silica, starch, etc.
  • binders hydroxypropylcellulose, polyvinylpyrrolidone, magnesium aluminate metasilicate, etc.
  • Disintegrating agents denpene, L-hydroxypropylcellulose, carboxymethylcellulose, croscarmellose sodium, calcium calcium glycolate, etc.
  • lubricants magnesium stearate, etc.
  • adhesives hydroxypropylcellulose, hydride
  • Roxypropylmethylcellulose Carbopol, Carboxymethyl Cellulose, Polyvinyl alcohol, Xanthan gum, Gua gum, etc.
  • Adhesion aids (glucose, fructose, mannitol, xylitol) Erythritol, maltose, trehalose, phosphate, kenate, cate, glycine, glutamic acid, arg
  • coating agent sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methyl cell
  • coating agent may be covered with a mouthful rate, etc., or may be covered with two or more layers.
  • additives such as preservatives, antioxidants, coloring agents, and sweetening agents that are commonly used can be added as necessary.
  • the intraoral quick disintegrating tablet is prepared according to a known method.
  • one or more active substances can be used as is, or a coating agent (ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, acrylic acid methacrylate copolymer) suitable for raw powder or granulated raw powder particles.
  • Plasticizers polyethylene glycol, triethyl citrate, etc.
  • active substances coated with excipients lactose, mannitol, glucose, microcrystalline cellulose, colloidal silica, denpun, etc.
  • binding Agents hydroxypropylcellulose, polyvinylpyrrolidone, magnesium aluminate, etc.
  • disintegrators starch, L-hydroxypropyl pillcellulose, carboxymethylcellulose, croscarmellose sodium, calcium fibrinoglycolate, etc.
  • Rejuvenating agents magnesium stearate, etc.
  • dispersing aids glucose, fructose, mannitol, xylitol, erythritol, maltose, trehalose, phosphate, kenate, cate, glycine, Glutamic acid, arginine, etc.
  • Stabilizer Polyethylene glycol, Propylene glycol, Glutamic acid, Aspartic
  • a coating agent sucrose, gelatin, hydroxypropylcellulose, hydroxypropylpyrumethylcellulose phthalate, etc.
  • additives such as preservatives, antioxidants, coloring agents, sweeteners, etc., which are commonly used can be added as necessary.
  • Liquid preparations for internal use for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups, elixirs and the like.
  • one or more active substances are added to the commonly used diluent (purified water, ethanol). Or a mixture thereof, etc.).
  • this liquid preparation may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffering agent and the like.
  • Examples of external dosage forms for parenteral administration include ointments, gels, creams, poultices, patches, liniments, sprays, inhalants, sprays, aerosols, eye drops And nasal drops. These contain one or more active substances and are prepared by known methods or commonly used formulations.
  • the ointment is produced by a known or commonly used formulation. For example, it is prepared by grinding or melting one or more active substances into a base.
  • the ointment base is selected from known or commonly used ones. For example, higher fatty acids or higher fatty acid esters (adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, oleic acid ester, etc.), wax (E.g., beeswax, spermaceti, ceresin, etc.), surfactants (e.g., polyoxyethylene alkyl ether phosphates), higher alcohols (e.g., sequinol, stearyl alcohol, cetostearyl alcohol), silicone oil (e.g., dimethylpolysiloxane) , Hydrocarbons (hydrophilic petrolatum, white petrolatum, purified lan
  • the gel is produced by a known or commonly used formulation. For example, it is prepared by melting one or more active substances in a base.
  • Gel base Is selected from known or commonly used ones. For example, lower alcohols (ethanol, isopropyl alcohol, etc.), gelling agents (carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, etc.), neutralizing agents (triethanolamine, diisoprono) Lumamine, etc.), surfactants (polyethylene glycol monostearate, etc.), gums, water, absorption promoters and anti-rash agents are used alone or in admixture of two or more. In addition, preservatives, antioxidants, flavoring agents, and the like may be included.
  • the cream is produced by a known or commonly used formulation. For example, it is produced by melting or emulsifying one or more active substances in a base.
  • the cream base is selected from known or commonly used ones. For example, higher fatty acid esters, lower alcohols, hydrocarbons, polyhydric alcohols (propylene glycol, 1,3-butylene glycol, etc.), higher alcohols (2-hexyldecanol, cetanol etc.)
  • emulsifiers polyoxyethylene alkyl ethers, fatty acid esters, etc.
  • water, absorption accelerators, and rash prevention agents may be used alone or in admixture of two or more. Further, it may contain a preservative, an antioxidant, a flavoring agent and the like.
  • the poultice is produced by a known or commonly used formulation. For example, it is produced by melting one or more active substances in a base material, and spreading and applying the mixture on a support.
  • the compress base is selected from known or commonly used ones. For example, thickeners (polyacrylic acid, polyvinylpyrrolidone, gum arabic, starch, gelatin, methylcellulose, etc.), wetting agents (urea, glycerin, propylene glycol, etc.), fillers (kaolin, zinc oxide, talc, calcium, magnesium) Etc.), water, a solubilizing agent, a tackifier, and a rash prevention agent are used alone or in admixture of two or more.
  • the patch may contain preservatives, antioxidants, flavoring agents and the like.
  • the patch is produced by a known or commonly used formulation. For example, it is produced by melting one or more active substances in a base and spreading them on a support.
  • the patch base is selected from known or commonly used ones. For example, those selected from polymer bases, fats and oils, higher fatty acids, tackifiers and anti-rash agents may be used alone or in admixture of two or more. Further, it may contain a preservative, an antioxidant, a flavoring agent and the like.
  • the liniment is produced by a known or commonly used formulation.
  • one or more active substances are dissolved in water, alcohol (ethanol, polyethylene glycol, etc.), higher fatty acid, glycerin, soap, emulsifier, suspending agent, etc.
  • it may contain a preservative, an antioxidant, a flavoring agent and the like.
  • Sprays, inhalants, and sprays are commonly used diluents as well as buffers that make them isotonic with stabilizers such as sodium bisulfite, such as sodium chloride, sodium citrate, or citrate.
  • An isotonic agent such as The method for producing the spray is described in detail, for example, in US Pat. Nos. 2,868,691 and 3,095,355.
  • Injectables for parenteral administration include all injections and drops.
  • intramuscular injection subcutaneous injection, intradermal injection, intraarterial injection, intravenous injection, intraperitoneal injection, spinal cavity injection, Intravenous drops.
  • injections for parenteral administration include solutions, suspensions, emulsions, and solid injections that are used by dissolving or suspending in solutions for use.
  • Injectables are used by dissolving, suspending or emulsifying one or more active substances in a solvent.
  • the solvent include distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof.
  • this injection is a stabilizer, solubilizing aid Agents (glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), suspending agents, emulsifying agents, soothing agents, buffering agents, preservatives, etc. They are sterilized in the final step or prepared by aseptic manipulation.
  • aseptic solid preparations such as lyophilized products can be produced and used by dissolving them in sterilized or sterile distilled water for injection or other solvents before use.
  • Eye drops for parenteral administration include eye drops, suspension eye drops, emulsion eye drops, in-use eye drops and eye ointments.
  • Eye drops include isotonic agents (sodium chloride, concentrated glycerin, etc.), buffering agents (sodium phosphate, sodium acetate, etc.), surfactants (polysorbate 80 (trade name), polyoxyl stearate 40, Polyoxyethylene hydrogenated castor oil, etc.), stabilizers (sodium citrate, sodium edetate, etc.), preservatives (benzalkonium chloride, parabens, etc.) and the like may be appropriately selected as necessary. These are sterilized in the final process or prepared by aseptic manipulation. In addition, an aseptic solid preparation, for example, a freeze-dried product can be produced and used by dissolving it in sterilized or aseptic sterilized purified water or other solvent before use.
  • isotonic agents sodium chloride, concentrated glycerin, etc.
  • buffering agents sodium phosphate, sodium acetate, etc.
  • surfactants polysorbate 80 (trade name), polyoxyl stearate 40, Polyoxyethylene hydrogen
  • Inhalants for parenteral administration include aerosols, inhalation powders or inhalation solutions, which are used by dissolving or suspending in water or other suitable medium at the time of use. Form may be sufficient.
  • preservatives benzalkonium chloride, parabens, etc.
  • coloring agents for example, coloring agents, buffering agents (sodium phosphate, sodium acetate, etc.), isotonicity It is prepared by appropriately selecting an agent (salt sodium salt, concentrated glycerin, etc.), a thickener (cariboxyvinyl polymer, etc.), an absorption accelerator and the like as required.
  • lubricants stearic acid and its salts, etc.
  • binders starch, dextrin, etc.
  • excipients lactose, cellulose, etc.
  • coloring agents antiseptics (salts) Hibenzarukonium, paraben, etc.
  • absorption enhancers etc.
  • a nebulizer (atomizer or nebulizer) is usually used to administer an inhalation solution, and an inhaler for powder medicine is usually used to administer a powder for inhalation.
  • compositions for parenteral administration include suppositories for rectal administration and pessaries for intravaginal administration, which contain one or more active substances and are prescribed by conventional methods.
  • the compound according to the present invention is useful as a prophylactic and / or therapeutic agent for a neuropsychiatric disease such as a disease caused by stress, depression, anxiety disorder or psychosomatic disease, which has no side effects.
  • Figure 1 shows the increase in corticosterone, 3- (2- (((((1 R)-1-(3,5-dimethylphenyl) 1 3-methylptyl) amino) carbonyl) 1 4 1 (5— Fluoro-2-methylphenoxymethyl) phenyl) propanoic acid (compound (1)), 3- (2 — (((1 R) — 3-methyl-1- (3,5-dimethylphenyl) butyl) 1) — (2,5-Difluorophenoxymethyl) phenyl) propanoic acid (compound (II)) and 3— (2 — (((1R) 1 3-methyl-1- (3,5-dimethyl) Phenyl) Butyl) Powered rubermoyl) 1 4- (2,5-Dimethylphenoxymethyl) Phenyl) Propanoic acid (Compound The product (III)) was suppressed by administration of 1 Omg / kg.
  • Figure 2 shows the results of the compound (I) significantly lowering the emotional excess score.
  • Figure 3 shows the results of a significant improvement in Compound (I) shortening the stay time in the open arm in the elevated plus maze.
  • the chromatographic separation location and the solvent in the chocolate shown in the TLC indicate the elution solvent or developing solvent used, and the percentages represent the volume ratio.
  • the solvent in the box shown in the NMR section indicates the solvent used for the measurement.
  • Example 7 3- (4- (2,5-Difluorophenoxymethyl) 1-2 — (((((1 R) -1- (naphthalene-2-yl) ethyl) amino) carbonyl) phenyl Propanoic acid
  • Example 7 3- (2-(((((1 R)) 1 1 1 (3,5_dimethylphenyl) —3-methylbutyl) amino) carbonyl) 1 4 1 (5-fluoro-2-methylsulfone Enoxymethyl) Phenyl) Propanoic acid
  • Example 7 (4): 3— (4 1, (2,5-Difluorophenoxymethyl) —2— (((4- (2- (3-Fluorophenyl) ethyl) tetrahydrone 2 ⁇ -pyran 1 41) Amino) Carbonyl) Phenyl) Propanoic acid
  • Example 7 3— (2- ((((1 R) — 1) (3,5-dimethylphenyl) —3—Methylptyl) amino) carbonyl) mono 4— (3-pyridyloxymethyl) phenyl) propanoic acid
  • Example 7 3- (4- (6-Fluoroindole 1-ylmethyl) ⁇ 2-((((1 R) — 1 (3,5-dimethylphenyl) 1 3-methylptyl ) Amino) Carbonyl) Phenyl) Propanoic acid
  • Example 11 Using the compound (1 Og) produced in Example 11, the same operation as in Example 6 was carried out to obtain the title compound (I5.9 g) having the following physical property values.
  • Example 15 4- (2-((((1R) —1— (Naphthalene-1-yl) ethyl) amino) carbonyl) 1-4-methoxymethoxyphenyl) butanonitryl
  • Anhydrous dimethyl sulfoxide (10 OmL) was stirred at 80 ° C for 5 hours. Water was added to the reaction mixture in an ice bath, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was crystallized from t-butyl methyl ether / hexane to obtain the title compound (10.2 g) having the following physical property values.
  • Example 16 4— (2— ((((1R) 1 1 (Naphthalene 1 1 yl) ethyl) amino) carbonyl) 1 4-methoxymethoxyphenyl) butanoic acid
  • Example 17 4- (2 — (((((1 R) 1 1 1 (Naphthalene 1 1 1yl) ethyl) amino) carbonyl) 1 4-hydroxyphenyl) butanoic acid methyl ester prepared in Example 16
  • methanol 4 OmL
  • concentrated sulfuric acid lmL
  • water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was crystallized from hexane to obtain the title compound (6.45 g) having the following physical property values.
  • Example 18 Under argon substitution, a solution of the compound prepared in Example 18 (5.57 g) in dimethyl sulfoxide (30 mL) was added to ethyl acrylate ester (3.60 mL), palladium acetate (II) (186 mg), 1, 1, 1 bis ( Diphenylphosphino) Phenocene (46 Omg) and triethylamine (11.6 mL) were added, and the mixture was stirred at 80 ° C for 4 hours. Ethyl acetate and water were added to the reaction mixture, and the mixture was filtered through Celite (registered trademark). The filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (5.33 g) having the following physical property values.
  • T L C R f 0.70 (ethyl acetate);
  • Example 22 4— (1,3—Dioxindan-5-yloxy) 1 2- (((((1 R) — 1 1 (Naphthalene 1-yl) ethyl) amino) carbonyl) phenyl ) Butanoic acid methyl ester
  • Example 22 Using the compound (80 mg) produced in Example 22, the title compound (74 mg) having the following physical data was obtained by the same procedures as in Example 7.
  • Example 11 Using the compound prepared in 1 and the corresponding compound, Example 12 ⁇ Example 17 ⁇ Example 22—The same procedure as in Example 23 was performed, or the compound prepared in Example 20 and the corresponding compound were prepared.
  • Example 1 2 ⁇ Example 22 ⁇ Perform the same operation as in Example 23, or use the compound produced in Example 11 1 or the compound produced in Example 21 and the corresponding compound.
  • Example 1 2 ⁇ Example 1 3 ⁇ Example 14 ⁇
  • Example 23 The same compounds as in Example 23 were obtained.
  • Example 23 3- (4- (3,5-dimethylphenylamino) -1-(-(((4- (Naphthalene-2-yl) tetrahydro-2- (4-naphthyl) -4-yl) Amino) carbonyl) phenyl) propanoic acid
  • Example 23 3— (4— (3,5-dimethylphenylamino) 1-2 (((1 R) 1-111 (3,5-dimethylphenyl) -1-3-methylptyl) amino) Force rubonyl) phenyl) propanoic acid
  • ⁇ 3 antagonists include compounds (I): 3— (2— ((((1 R)-1 (3,5-dimethylphenyl) —3-methylmethyl) amino) carbonyl) 1 4 1 (5— Fluoro-2-methylphenoxymethyl) phenyl) propanoic acid, compound (II): 3— (2— (((1 R) —3—methyl-1— (3, 5—dimethylphenyl) butyl) force rubamoyl) 4-((2,5-Difluorophenoxymethyl) phenyl) propanoic acid or compound (III): 3- ((2-. (((1 R)-(3- (R)) ) Ptyl) Forced Lubamoyl) 4- (2,5-Dimethylphenoxymethyl) phenyl) Propanoic acid was used.
  • Example 24 Inhibitory effect on sulprostone-induced corticosterone elevation
  • the EP 3 antagonist of the present invention [compound (1), compound (11), or compound (III) (each 10 mg / 5 mL / kg (0.5% methylcellulose suspension) )] was orally administered to the control group and 0.5% methylcellulose suspension (5 mL / kg) was orally administered 1 hour after administration, sulprostone (0.3 mg / 4 mL / kg) was subcutaneously administered to all groups.
  • 0.5% methylcellulose suspension (5 mL / kg) was orally administered to the non-induced group, and physiological saline (4 mg) was subcutaneously administered 1 hour after administration.
  • any of the compounds according to the present invention significantly suppressed the increase in the amount of corticosterone.
  • Example 25 Antidepressant and anxiolytic effects on olfactory bulbectomized rats
  • the sham-operated animals like the olfactory bulb-extracted animals, were intoxicated, fixed to the brain, and incised on the scalp. After making holes in the left and right olfactory bulbs, the scalp was sutured without aspiration / removal of the olfactory bulb. After olfactory bulbectomy, the animals were kept alone. On the other hand, sham-operated animals were not isolated.
  • the compound (I) according to the present invention 5 mg / kg
  • the target compound. (Decibramin hydrochloride (1 Omg / kg); Wako Pure Chemical Industries, Ltd.), and the control (0.5% methyl) Cellulose (5 mL / kg) was orally administered twice a day for 7 days each.
  • the emotional hyperreactivity was evaluated by the Gomi et al. Method (Ami Gomida, 4 others, Nippon Pharmacology Journal, 1983 Year, Vol. 82, p267-292). The result is shown in figure 2.
  • the olfactory bulb-extracted animal and sham-operated animal to which the compound (1), decibramin hydrochloride, and control according to the present invention were administered for 10 minutes from 1 hour after the first administration on the eighth day were respectively shown in the elevated plus maze. It was placed in the center of the platform facing the oven (Open) arm and measured for 5 minutes. The video image behavior analyzer was used to measure the time spent on the oven arm (seconds) and the time spent on the close arm (seconds). The results are shown in Figure 3.
  • the following components were mixed by a conventional method and then tableted to obtain 10,000 tablets each containing 1 Omg of the active ingredient.
  • the compound according to the present invention can be used as a prophylactic and / or therapeutic agent for a disease caused by stress, a neuropsychiatric disorder such as depression, anxiety disorder or psychosomatic disorder.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Addiction (AREA)
  • Pain & Pain Management (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Anesthesiology (AREA)
  • Cardiology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Pulmonology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne un agent préventif et/ou thérapeutique pour troubles psychonévrotiques, comprenant un antagoniste de l’EP3, représenté par la formule générale : (I) (où la signification des signes est définie dans la description). Ce composé a un pouvoir antagoniste contre l’EP3 et présente une efficacité grâce à un mécanisme d’action inhabituel en tant qu’agent préventif et/ou thérapeutique pour les maladies psychonévrotiques, tels que les troubles psychosomatiques, les troubles anxieux, la dépression et les troubles dus au stress.
PCT/JP2005/014792 2004-08-06 2005-08-05 Agent thérapeutique pour maladie psychonévrotique WO2006014024A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2006531749A JPWO2006014024A1 (ja) 2004-08-06 2005-08-05 精神神経系疾患治療剤
EP05770601A EP1787657A1 (fr) 2004-08-06 2005-08-05 Agent therapeutique pour maladie psychonevrotique
US11/659,480 US20090286862A1 (en) 2004-08-06 2005-08-05 Therapeutic agent for psychoneurotic disease

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2004230228 2004-08-06
JP2004/230228 2004-08-06

Publications (1)

Publication Number Publication Date
WO2006014024A1 true WO2006014024A1 (fr) 2006-02-09

Family

ID=35787295

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2005/014792 WO2006014024A1 (fr) 2004-08-06 2005-08-05 Agent thérapeutique pour maladie psychonévrotique

Country Status (4)

Country Link
US (1) US20090286862A1 (fr)
EP (1) EP1787657A1 (fr)
JP (1) JPWO2006014024A1 (fr)
WO (1) WO2006014024A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2018216640A1 (ja) * 2017-05-22 2020-03-26 小野薬品工業株式会社 Ｅｐ４アンタゴニスト

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ599464A (en) 2005-02-03 2014-03-28 Topotarget Uk Ltd Combination therapies using hdac inhibitors
CN102579417B (zh) 2005-05-13 2014-11-26 托波塔吉特英国有限公司 Hdac抑制剂的药物制剂
AU2006313517B2 (en) * 2005-11-10 2013-06-27 Topotarget Uk Limited Histone deacetylase (HDAC) inhibitors (PXD101) for the treatment of cancer alone or in combination with chemotherapeutic agent
US9150507B2 (en) 2006-04-28 2015-10-06 Shionogi & Co., Ltd. Amine derivative having NPY Y5 receptor antagonistic activity
MX2010003230A (es) * 2007-09-25 2010-04-07 Topotarget Uk Ltd Metodos para la sintesis de ciertos compuestos de acido hidroxamico.
SA08290668B1 (ar) 2007-10-25 2012-02-12 شيونوجي آند كو.، ليمتد مشتقات أمين لها نشاط مضاد لمستقبل npy y5 واستخداماتها
MX2010009642A (es) * 2008-03-07 2010-09-22 Topotarget As Metodos de tratamiento utilizando infusion continua prolongada de belinostat.
GB0900555D0 (en) * 2009-01-14 2009-02-11 Topotarget As New methods
US8227618B2 (en) 2009-04-23 2012-07-24 Shionogi & Co., Ltd. Amine-derivatives having NPY Y5 receptor antagonistic activity and the uses thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002016311A1 (fr) * 2000-08-22 2002-02-28 Ono Pharmaceutical Co., Ltd. Derives d'acide carboxylique, procede de production de ceux-ci et medicaments contenant ceux-ci comme principe actif
WO2002020462A1 (fr) * 2000-09-01 2002-03-14 Ono Pharmaceutical Co., Ltd. Derives d'acide benzoique et medicaments possedant ces derniers comme principe actif
WO2003016254A1 (fr) * 2001-08-09 2003-02-27 Ono Pharmaceutical Co., Ltd. Composes derives d'acide carboxylique et medicaments comprenant ces composes comme principe actif

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002016311A1 (fr) * 2000-08-22 2002-02-28 Ono Pharmaceutical Co., Ltd. Derives d'acide carboxylique, procede de production de ceux-ci et medicaments contenant ceux-ci comme principe actif
WO2002020462A1 (fr) * 2000-09-01 2002-03-14 Ono Pharmaceutical Co., Ltd. Derives d'acide benzoique et medicaments possedant ces derniers comme principe actif
WO2003016254A1 (fr) * 2001-08-09 2003-02-27 Ono Pharmaceutical Co., Ltd. Composes derives d'acide carboxylique et medicaments comprenant ces composes comme principe actif

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2018216640A1 (ja) * 2017-05-22 2020-03-26 小野薬品工業株式会社 Ｅｐ４アンタゴニスト
JP7211358B2 (ja) 2017-05-22 2023-01-24 小野薬品工業株式会社 Ｅｐ４アンタゴニスト

Also Published As

Publication number Publication date
JPWO2006014024A1 (ja) 2008-05-01
US20090286862A1 (en) 2009-11-19
EP1787657A1 (fr) 2007-05-23

Similar Documents

Publication Publication Date Title
WO2006014024A1 (fr) Agent thérapeutique pour maladie psychonévrotique
JP5387997B2 (ja) 血管の収縮または拡張による疾患治療剤
KR101663436B1 (ko) N-치환된 벤즈아미드 및 이의 사용 방법
WO2005040135A1 (fr) Medicament antistress et usage medical correspondant
JPWO2005047286A1 (ja) スピロ複素環化合物
TW201443005A (zh) 作爲鈉通道調節劑之醯胺
KR20010021853A (ko) 카파 효능제 화합물, 약제학적 제형 및 이를 이용한소양증의 예방 및 치료 방법
WO2013120438A1 (fr) Substance pour le traitement ou le soulagement de la douleur
CN101370380A (zh) 化合物
TW200831089A (en) Substituted bicyclocarboxyamide compounds
WO2004065365A1 (fr) Derives de 8-azaprostalangine et utilisations de ces derives en tant que medicaments
JP2012144545A (ja) アルファ−２−デルタリガンドとセロトニン／ノルアドレナリン再取込み阻害薬を含む組合せ
TW200810752A (en) Modulators of muscarinic receptors
WO2015032328A1 (fr) Dérivé indane, son procédé de préparation, et son application pharmaceutique
EP3480186B1 (fr) Nouveau dérivé d'aryléthène et composition pharmaceutique contenant ce dérivé comme principe actif
US20180256534A1 (en) Ketamine and cytochrome p 450 inhibitor combinations
RU2335490C2 (ru) Соединения карбоновой кислоты, фармацевтическая композиция на их основе, способ лечения и применение
JP2005511625A (ja) 向精神薬としてのピラゾール誘導体
JP2005511625A5 (fr)
WO2009105781A1 (fr) Procédés pour inhiber la dégradation de médicament
JP4236407B2 (ja) 生理活性なゲピロン代謝産物を使用することによって心理的疾患を治療する方法
JP5439817B2 (ja) 尿排出障害治療剤
WO2012088156A1 (fr) Inhibiteurs de cytochrome p450
JP2008255064A (ja) 睡眠障害予防治療剤
JP2008523137A (ja) セロトニンおよびノルアドレナリン再取込み阻害剤としてのｎ−ピロリジン−３−イル−アミド誘導体

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2006531749

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 11659480

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2005770601

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 2005770601

Country of ref document: EP